The transition from compensated hypertrophy to failure in spontaneously hypertensive rats (SHR) of advanced age is associated with a marked increase in collagen, a reduction in myocyte mass, and a reduction in maximum Ca2+ activated myofibrillar force. We hypothesized that the reduction in myocyte mass and associated functional loss may be due to increased cell death by apoptosis. To test this hypothesis, we studied hearts from failing and non-failing SHR (SHR-F and SHR-NF, respectively) and age-matched Wistar-Kyoto rats (WKY). In addition, hearts from SHR-F that had been treated with an angiotensin converting enzyme inhibitor (captopril) for an average of 27 days were also studied. Apoptotic cells were significantly increased in the SHR-F (38.9212.79 cells per 100,000 nuclei vs. 8.05 plus minus 3.98 in SHR-NF, plesser than<0.05; vs. 2.21 plus minus 1.4 in WKY, p lesser than 0.01). Captopril treatment of SHR-F rats reduced the number of apoptotic cells to that level in SHR-NF (4.25 plus minus 0.92 cells; p lesser than 01 vs SHR-F). Most apoptotic cells were of cardiac myocyte origin. There was no significant difference in Bcl-2 protein expression in hearts of the three groups. WAF-1 mRNA levels were increased in both SHR groups vs. WKY; in SHR-F the density of WAF-1 mRNA was higher than in SHR-NF. Thus, increased numbers of apoptotic cells are present in failing SHR hearts suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from stable compensation to heart failure in this model. Administration of the angiotensin converting enzyme inhibitor, captopril which ameliorates heart failure in this model, is associated with a reduction in the exaggerated apoptosis that accompanies the heart failure.